Human cytomegalovirus (HCMV) infects over 60% of the adult population. It is a major cause of birth defects, and a life-threatening opportunistic agent in immunosuppressed people. Congenital infection has a significant prevalence and can cause permanent disabilities -- hearing and vision loss, and mental retardation. Mass spectrometry-based proteomic analysis in our lab has recently revealed that numerous cell-surface proteins are dynamically modulated following HCMV infection of fibroblasts. The set of modulated proteins includes 27 proteins that are categorized as cell-surface adhesion proteins; and two upregulated adhesion proteins, L1CAM, a member of the IgCAM family of adhesion proteins, and GPR56, a member of the adhesion family of G protein coupled receptors, significantly impact the yield of HCMV progeny. Taken together, these observations form the foundation of the central hypothesis underlying this application: multiple cellular adhesion proteins cooperate to modulate the outcome of HCMV infection. To address this hypothesis, a systematic study to generate the first time-resolved functional view of multiple cell-surface adhesion proteins during HCMV infection is proposed. Mutually reinforcing systemic approaches that capture the big picture and reductionist approaches that facilitate testing specific hypotheses will be used. The big picture will be generated by identifying alterations to cell-surface adhesion proteins in multiple cell types following HCMV infection, determining whether the altered proteins impact the production of infectious progeny and evaluating their effect on infected cell adhesion and migration. Deep drills will lead to detailed elucidation of the functionl roles of specific cell-surface adhesion molecules, such as L1CAM and GPR56, during HCMV infection. Collectively, this study will provide the first broad-based, mechanistic characterizatio of adhesion proteins during HCMV infection. Successful completion of these studies should contribute importantly to the understanding of a relatively understudied area of HCMV biology, the role of cellular adhesion proteins in viral replication and dissemination. Cell surface protein comprise more than a third of the human proteome, they are often altered on diseased cells and they serve as targets for more than two-thirds of existing drugs. Therefore, it is very likely that enhanced understanding of the infected cell-surface proteome, with detailed delineation of the mechanistic roles of individual proteins that are altered by infection, will yield significant insihts to viral pathogenesis and identify previously unexplored targets for treatment of HCMV-related diseases.